Why do some individuals exposed to traumatic events develop Post-traumatic Stress Disorder (PTSD), while others do not? Risk and resilience are two concepts that are important in understanding the etiology of PTSD. Past research on PTSD has identified different factors that may put individuals at greater risk of developing PTSD, such as family history, childhood experiences, personality variables, and preexisting mental disorders. The concept of resilience, often considered to represent resistance to the negative effects of a traumatic event, is also very important in any consideration of PTSD. Resilience can be defined as "the ability to successfully adapt to stressors, maintaining psychological well-being in the face of adversity." Equally as important, however, is the concept of resilience as the ability to improve after the development of PTSD. The biological factors associated with the risk of developing PTSD, as well as both aspects of resilience are poorly understood. This project will investigate biological risk and resilience factors associated with the development of PTSD among a sample of Marines before and after they are exposed to combat stress utilizing genomic methodologies and a battery of behavioral and biological assessments. Specifically, we propose to investigate gene- expression based biomarkers of PTSD risk and resilience. The development of PTSD following initial traumatic exposure is quite variable, with some individuals never exhibiting signs of PTSD, while others are plagued with incapacitating symptoms despite years of combinations of therapy. At present, the basic characteristics underlying resilience are unknown, and it is not currently possible to predict the development of the disorder, much less any eventual outcome in any given individual. If biomarkers related to risk can be discovered, they may help to identify which individuals are at risk, and lead to more effective primary prevention protocols. Although environmental factors are clearly essential for the development of PTSD, the disorder also has a demonstrable genetic component. We plan in this study to identify gene-based biomarkers of PTSD in an effort to better understand the biological factors related to both the risk of developing PTSD;and to resilience as represented by resistance to development of PTSD. To accomplish these objectives, we have proposed two specific aims as follows: Specific Aim 1: Identify gene-expression-based biomarker profiles of PTSD risk and resilience in peripheral blood mononuclear cells and Specific Aim 2: Identify changes in gene-expression-based biomarker profiles of risk and resilience in peripheral blood mononuclear cells. PUBLIC HEALTH RELEVANCE: The development of Post Traumatic Stress Disorder (PTSD) following initial traumatic exposure is extremely variable. While some individuals never exhibit signs of PTSD, others are plagued with incapacitating symptoms despite years of combinations of therapy. Understanding the gene expression patterns of combat-exposed individuals who go one to experience PTSD, as compared to the gene expression patterns of combat-exposed individuals who did not go on to experience PTSD, will shed light on the biological mechanisms involved in PTSD and provide a basis for more effective prevention and treatment of this devastating disorder.